Primary Arterial Hypertension News - Menu Save Siti give her life
Annie Freeda Cruez KUALA LUMPUR, May 6, 2005— Siti Salmah Jasni has school books scattered all over her bed, like many students her age reviewing their lessons. Her bed, however, is in the Institute of Respiratory Medicine here, and she has tubes running into her nostrils, carrying oxygen to her lungs. The cheerful disposition of this Form Four student belies the truth. Siti Salmah is fighting for her life. Help must come quickly if the 16-year-old is to live: She is one of eight patients waiting for lungs and transplant operations. "I want to live. I want to go to school just like all my friends. I want to study, to play and to go out," said Siti Salmah, who has suffered from asthma since she was one. Tears welled up in her eyes, despite her brave front. It has been a year since Siti Salmah first realised something was wrong. A student of Sekolah Tengku Abdul Rahman Putra, in Kulai, Johor, she was short of breath all the time and found it difficult to climb the staircase in school. Doctors in Kulai Hospital, where she had been referred, could not find anything wrong. Siti Salmah, however, continued to suffer breathlessness, fatigue, giddiness and of being lethargic. Her condition worsened day by day. After a battery of tests in December, doctors at the Sultanah Aminah Hospital, Johor Baru, found that the blood pressure in her lungs was above normal. Called primary pulmonary hypertension, her condition is considered a genetic disorder and it could lead to heart failure and eventually death. In March, she was admitted to the Institute of Respiratory Medicine. "We need to replace her lungs as soon as possible," said Dr Ashari Yunus, who is treating Siti Salmah. Heart, lung and cornea transplants need cadaveric organs and not those of living donors. But with few voluntary organ donors, and many families unwilling to agree to donate dead relatives' organs, it will be difficult for Siti Salmah. For the last two months, she has been hooked up to a machine that pumps precious oxygen into her body. Without it, she would turn blue. Last month, she was discharged. She returned to Johor, and was admitted to the Kulai Hospital where she has been ever since. Her family does not have the RM9,000 needed to buy a static oxygen tank for her to use at home, and a portable one so she can go to school. Siti Salmah has an elder sister who is in Form Five, and a younger sister in Form Two. Their father is a lorry driver who earns just enough to make ends meet. Today, Siti Salmah endured a five-hour drive to the Institute here for a scheduled check-up. She brought her school books with her. She is looking beyond her ill-health, and is determined to sit for her Sijil Pelajaran Malaysia examinations next year. Her mother, housewife Sabariah Mustafa, 47, was diagnosed with the same condition seven years ago, but her condition is not as critical as her daughter's.
To pledge organs or donate organs of deceased relatives, please contact the National Transplant Resource Centre at 1800-88-9080 (toll-free) or 03-2694 2704/5. To donate funds, please send a cheque payable to New Straits Times with Siti Salmah's name written on the reverse side and addressed to: The Cashier, Finance Department/ Charity Unit, The New Straits Times Press (M) Bhd, Balai Berita, 31, Jalan Riong, 59100 Kuala Lumpur.
Drugs in Development
Significant milestone
by Neal Bellucci
GlaxoSmithKline has commenced a worldwide clinical trial to investigate the safety and efficacy of eltrombopag as a once-daily, orally administered drug for adult patients with previously treated idiopathic thrombocytopenic purpura — a disorder characterized by low platelet counts, leaving patients at risk for episodes of spontaneous bruising, mucosal bleeding, and in severe cases, intracranial hemorrhage. Trial sites are in 33 countries, including Italy, Denmark, Poland, France, Germany, the United Kingdom, Spain, Switzerland, Russia, the Netherlands, Hong Kong, Pakistan, Mexico, Australia, the United States, and Canada.
Subjects will be randomized to receive eltrombopag or placebo once daily for six weeks. The study population will include adults with idiopathic thrombocytopenic purpura, diagnosed at least six months prior to screening, who have platelet counts of less than 30,000/microL and who have not responded to previous treatment or have relapsed within three months of previous treatment.
Eltrombopag is an investigational small-molecule thrombopoietin receptor agonist that is thought to stimulate the proliferation and differentiation of megakaryocytes, the bone-marrow cells that give rise to blood platelets, and thus is considered a platelet-growth factor. Because it is a small molecule, the drug is administered orally as a tablet and has less potential than large protein molecules for causing an immune system reaction. Eltrombopag was discovered through a research collaboration between GlaxoSmithKline and Ligand Pharmaceuticals. The drug is being developed by GlaxoSmithKline.
"Data to date demonstrates that eltrombopag may be effective in increasing platelet counts in patients with chronic ITP and this trial will help us to further evaluate its potential," says Paolo Paoletti, M.D., senior VP, oncology medicine development center, GlaxoSmithKline (gsk.com).
Top line results of the Phase II trial in idiopathic thrombocytopenic purpura — which had a similar design as the Phase III trial, but tested various dosing levels — were reported in December 2005. The study of 97 patients found that eltrombopag, at doses of 75 milligrams and 50 milligrams, compared with placebo, was successful in increasing platelet count from a baseline of less than 30,000/microL to at least 50,000/microL after 42 days of dosing. The 30-milligram dose showed limited change from baseline. In addition, there were no safety or tolerability events that would preclude advancement to Phase III studies.
A reduction in platelet count is the defining characteristic of any type of thrombocytopenia and diagnosis can be confirmed following a routine blood test. Idiopathic thrombocytopenic purpura is an autoimmune disorder that is marked by platelet destruction and/or inadequate platelet production. The onset of symptoms is sometimes unpredictable and patients suffering from thrombocytopenia may be asymptomatic. Thrombocytopenia also can occur as a consequence of chemotherapy treatment, interferon treatment, or chronic liver disease. The prevalence of the disease is not well-established, and there are very few published epidemiologic studies of this disease in the United States. An internal study of a managed-care population in the United States estimated the prevalence of chronic idiopathic thrombocytopenic purpura at around 77,000 cases.
Thrombocytopenia can impede a variety of medical treatments, including preventing cancer patients from receiving their full dose of chemotherapy, preventing patients with hepatitis C infection from receiving interferon therapy or lead to dose reductions or discontinuation, and it can prevent or complicate procedures in patients with chronic liver disease and idiopathic thrombocytopenic purpura.
In another development for GlaxoSmithKline, the company has signed a two-part collaboration deal with Myogen Inc. in pulmonary arterial hypertension.
Myogen (myogen.com) licensed commercialization rights for ambrisentan, its selective endothelin receptor antagonist in Phase III development, to GlaxoSmithKline in all territories outside of the United States. Filing for marketing approval in the United States and Europe is expected later this year. Simultaneously, GlaxoSmithKline and Myogen entered a distribution agreement whereby Myogen will be responsible for the U.S. marketing and distribution of GSK’s Flolan, which is used in the treatment of pulmonary arterial hypertension.
In the ambrisentan license agreement, Myogen will receive an upfront payment of $20 million and, subject to the achievement of specific milestones, will be eligible to receive up to an additional $80 million in milestone payments. In addition, Myogen will also receive stepped royalties on product sales with an estimated average royalty in the mid-20% range.
Myogen will be responsible for the continued clinical development of ambrisentan. GlaxoSmithKline will be responsible for all regulatory and commercial expenses in its licensed territories. The companies will share the costs of certain additional clinical development activities for ambrisentan.
Ambrisentan is being developed as a once-daily oral therapy for patients with pulmonary arterial hypertension and has been granted orphan-drug designation in the United States and European Union. Filing with FDA and EMEA are targeted for fourth-quarter 2006.
The investigational drug is a non-sulfonamide, propanoic acid-class, type-A selective endothelin receptor antagonist. Endothelin is a small-peptide hormone that plays a critical role in the control of blood flow and cell growth. Elevated endothelin blood levels are associated with several cardiovascular disease conditions, including pulmonary arterial hypertension, chronic renal disease, coronary artery disease, hypertension, and chronic heart failure. Agents that block the detrimental effects of endothelin may provide benefits in the treatment of these conditions.
Under the terms of the Flolan distribution agreement, Myogen will build a commercial support team and field sales organization beginning second-quarter 2006 dedicated to the marketing and distribution of Flolan in the United States. The three-year distribution agreement comes with an option to renew upon mutual consent.
Flolan was approved by FDA in 1995 and is indicated for the long-term intravenous treatment of primary pulmonary hypertension and pulmonary hypertension associated with the scleroderma spectrum of disease in NYHA Class III and Class IV patients who do not respond adequately to conventional therapy.
Phase III trials
Promise for clot drug
Patient enrollment has begun for a second pivotal Phase III clinical trial of alfimeprase for the treatment of central venous catheter occlusion. Alfimeprase is a novel thrombolytic, or blood-clot dissolver, jointly developed by Bayer HealthCare AG and Nuvelo Inc.
The study is the second of two overlapping, multinational trials in the Phase III alfimeprase program. This open-label, single-arm trial will evaluate the safety and efficacy of 3 milligrams of alfimeprase in 800 patients with occluded central venous catheters.
In January 2006, Bayer and Nuvelo entered a collaboration agreement for the global development and commercialization of alfimeprase. Under the terms of the agreement, Bayer (bayerhealthcare.com) will commercialize alfimeprase in all territories outside the United States.
"We believe that alfimeprase has the potential to quickly dissolve clots and rapidly restore the ability to infuse critical therapy such as chemotherapy or antibiotics through once-occluded catheters," says Steven R. Deitcher, M.D., VP, medical sciences, Nuvelo (nuvelo.com). "We look forward to completing the first trial in this program, Sonoma-2, later this year and expect the Phase III trial results to confirm the ability of alfimeprase to restore function to occluded catheters in 15 minutes or less, as demonstrated in our Phase II trial."
Results from a Phase II multi-center, randomized, double-blind study in 55 patients with occluded central venous catheters demonstrated that alfimeprase restored flow to 40% and 50% of occluded catheters 5 minutes and 15 minutes after the first dose. Additionally, alfimeprase restored flow to 60% of occluded catheters at 120 minutes after the first dose and to 80% of occluded catheters at 120 minutes after the second dose compared with 46% at 120 minutes after the first dose and 62% at 120 minutes after the second dose with Genentech’s Cathflo Activase.
Delivery of chemotherapy, nutritional support, antibiotics, and blood products, as well as the frequent withdrawal of blood samples for laboratory testing, are often facilitated via central venous catheters. About 5 million catheters are placed in patients in the United States each year, with as many as 25% becoming occluded. When a catheter becomes occluded, the goal is to restore flow in a prompt and cost-effective manner with minimal risk to the patient.
As these catheters are primarily inserted in patients receiving life-saving medications such as chemotherapy, it is critical to restore flow through the catheter as soon as possible. In the case of thrombotic occlusions, treatment with thrombolytic drugs represents a less-invasive and more cost-effective alternative to replacement. Currently, Cathflo Activase is approved in the United States for restoring function to central venous catheters.
The first study in the ongoing Phase III clinical program in central venous catheter occlusion began in September 2005 and is expected to complete enrollment in the second half of this year. This randomized, double-blind study is comparing the efficacy of 3 milligrams of alfimeprase with placebo in 300 patients with occluded central venous catheters. The primary endpoint is restoration of catheter function within 15 minutes.
Alfimeprase is also being studied in an ongoing Phase III program for the treatment of acute peripheral arterial occlusion, or "leg attack." The program consists of two overlapping, randomized, double-blind, multinational trials comparing 0.3 mg/kg of alfimeprase with placebo in a total of 600 patients. The primary endpoint is avoidance of open vascular surgery within 30 days of treatment.
Another collaboration
Monogram Biosciences Inc. is collaborating with Merck & Co. by providing its PhenoSense and GeneSeq testing technologies for use in Phase III trials of MK-0518, Merck’s investigational HIV-1 integrase inhibitor.
MK-0518 is a novel compound with the potential to be the first in a new class of anti-retroviral drugs for the treatment of HIV/AIDS. Integrase inhibitors are designed to block HIV from replicating by preventing the viral enzyme integrase from inserting HIV DNA into the human genome.
MK-0518 entered Phase III development early this year. The Phase III studies will take place at sites in North America, Central America, South America, Europe, Australia, and Asia.
"We are very pleased to be initiating our Phase III program for MK-0518," says Daria Hazuda, VP, virus and cell biology, Merck Research Laboratories (merck.com). "We have chosen to collaborate with Monogram Biosciences for HIV phenotypic and genotypic testing because of their expertise in developing technologies critical for optimizing patient therapy and evaluating drug resistance."
Drug resistance will be evaluated using Monogram’s PhenoSense GT, as well as other phenotypic and genotypic assays and clinical trial services. The MK-0518 study joins Monogram’s extensive portfolio of drug development testing for new and promising classes of HIV antiretroviral therapies.
"Merck and Monogram have been close collaborators in HIV resistance for many years and we are very happy to again be supporting the clinical development of a potentially important new HIV therapy," says Christos J. Petropoulos, chief scientific officer, Monogram Biosciences (monogrambio.com). "The manner in which Merck is applying our tests is exactly as we intended, initially for the evaluation of new drug classes and subsequently for optimizing treatment regimens."
Monogram’s products are designed to help doctors optimize treatment regimens for their patients that lead to better outcomes and reduced costs. The company’s technology is also being used by numerous biopharmaceutical companies to develop new and improved antiviral therapeutics and vaccines as well as targeted cancer therapeutics.
First study started
The first of two Phase III clinical trials required for registration of pancreatic enzyme product EUR-1008M has been initiated by Eurand Inc. EUR-1008M is being studied in patients with exocrine pancreatic insufficiency, a deficiency of digestive enzymes normally produced by the pancreas, which leads to malnutrition, impaired growth, and shortened life expectancy. Exocrine pancreatic insufficiency can result from a number of diseases and conditions, including cystic fibrosis, chronic pancreatitis, and pancreatic cancer.
EUR-1008M has been developed as a delayed-release capsule intended to provide consistent product-dosing over time and will be available in multiple dosage strengths. EUR-1008M consists of about 14 enzymes, coenzymes, and cofactors, is biologically similar to endogenous human pancreatic secretions and is intended to treat malabsorption of fats, proteins, carbohydrates, and other essential nutrients in patients with pancreatic insufficiency.
The trial will involve about 20 clinical study sites in the United States. Patient enrollment is expected to be complete by the end of June 2006, and results are expected in the fourth quarter of 2006. The trial is designed to determine the safety and tolerability of EUR-1008M and will compare the active drug to placebo in improving absorption of fat and other nutrients.
"The commencement of these trials is a major milestone in our development of a new PEP formulation for the treatment of pancreatic insufficiency," says Gearoid Faherty, CEO, Eurand (eurand.com).
"This new product builds on our 15 years of experience in developing and manufacturing pancreatic enzyme products and we believe that if these Phase III trials are successful, EUR-1008M could represent a significant advance in the treatment of pancreatic insufficiency."
An additional trial of EUR-1008M in a pediatric population is expected to commence in the second quarter of 2006.
Current treatment of pancreatic insufficiency requires the use of pancreatic enzyme products. No marketed products in the United States have been approved by FDA, and FDA has issued regulations requiring all pancreatic enzyme products marketed after April 2008 to have an FDA-approved registration.
Eurand boasts annual revenue of more than $100 million. Based in Milan, Italy, the company has research, development, and manufacturing facilities throughout the world, including sites in Milan, Vandalia, Ohio, and Paris.
Orphan-drug designation
Potential supported in EU
AS1411, an aptamer drug in development by cancer drug company Antisoma, has been granted orphan-drug status in the European Union for the treatment of renal and pancreatic cancers. This will provide a 10-year period of market exclusivity if AS1411 is approved as a treatment for either disease.
The drug already has received orphan-drug status in the United States for renal and pancreatic cancers. AS1411 has shown promise in patients with renal cancer: of three who participated in a Phase I trial, two showed long-term stable disease and one a near-complete response. An extension of this trial is recruiting additional renal cancer patients and will yield new data during 2006.
Antisoma expects renal cancer to be an important indication for later-stage trials. The company will seek to conduct an accelerated clinical development program. Pancreatic cancer is one of a number of other cancers in which there are supportive preclinical data for AS1411. These include solid and blood cancers.
Antisoma is working to identify which indications should receive the highest priority for entry into Phase II trials. Conventional Phase II studies in other cancers would likely run in parallel with any expedited program in renal cancer.
"Receipt of EU orphan-drug status for renal and pancreatic cancers supports our view that AS1411 has potential against a variety of cancers," says Glyn Edwards, CEO, Antisoma (antisoma.com). "The drug’s early promise in renal cancer has opened up the possibility of rapid progress towards the market in this indication, so we are particularly pleased that we now have orphan status for renal cancer on both sides of the Atlantic."
Back on track
Clinical hold lifted
Biogen Idec and Elan Corp. were informed by FDA that the agency has removed the hold on clinical trial dosing of Tysabri, composed of natalizumab, for multiple sclerosis in the United States.
The companies expect to begin an open-label, multi-center safety extension study of Tysabri monotherapy in the United States and internationally in the coming weeks. Patients who previously participated in the Phase III multiple sclerosis program are eligible for entry.
The FDA’s peripheral and central nervous system drugs advisory committee voted in early March to support the drug’s return to market. A final agency decision was expected by the end of the month.
Tysabri was approved by FDA and launched in November 2004 for the treatment of patients with relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations.
Biogen Idec (biogenidec.com) and Elan had voluntarily suspended Tysabri from the U.S. market and all ongoing clinical trials based on reports of progressive multifocal leukoencephalopathy, a rare and potentially fatal, demyelinating disease of the central nervous system. Biogen Idec and Elan (elan.com) completed a comprehensive safety evaluation of more than 3,000 Tysabri patients in collaboration with leading experts in progressive multifocal leukoencephalopathy and multiple sclerosis. The results of the safety evaluation yielded no new confirmed cases of progressive multifocal leukoencephalopathy.
On Sept. 26, 2005 the companies submitted a supplemental biologics license application to FDA. Subsequently, FDA designated Tysabri for priority review, which the agency grants to products that are considered to be potentially significant advancements over existing therapies that address unmet medical needs.
Off their tracks
Enrollment suspended
Genentech Inc. suspended enrollment into Avant, an international Phase III study of Avastin, Xelox, and Folfox chemotherapy regimens in early-stage colon cancer, to enable the data safety monitoring board to review 60-day safety data.
The board’s recommendations are based on adverse events observed at a higher rate in the Xelox/Avastin arm of the study compared to the other two arms of the study. In addition, the rapid recruitment in the Avant trial could prevent an adequate and timely safety assessment.
Excluding deaths due to recurrent colon cancer, all-cause mortality was 0.6% for the Folfox arm, 0.4% for the Folfox/Avastin arm, and 1% for the Xelox/Avastin arm. An occurrence of cardiac and unknown deaths, some of which occurred in younger patients, was noted in the Xelox/Avastin arm.
Since the Avant trial began recruitment in December 2004, almost two-thirds of the target number of 3,450 patients have been enrolled. In January 2006 alone, more than 250 patients were recruited.
The board will continue to monitor all adverse events in the study, including gastrointestinal perforations, an adverse event observed in studies of Avastin plus chemotherapy that has been observed in Avastin-treated patients in the Avant study at a rate of about 1%. This is less than what was observed in the metastatic setting.
"We believe the board’s recommendation to temporarily suspend enrollment in the study is the right thing to do for patients in order to enable a more detailed analysis of safety data," says Hal Barron, M.D.,senior VP, development, and chief medical officer, Genentech (gene.com).
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